Burette Melanie, Allombert Julie, Lambou Karine, Maarifi Ghizlane, Nisole Sébastien, Di Russo Case Elizabeth, Blanchet Fabien P, Hassen-Khodja Cedric, Cabantous Stéphanie, Samuel James, Martinez Eric, Bonazzi Matteo
Institut de Recherche en Infectiologie de Montpellier (IRIM) UMR 9004, CNRS, Université de Montpellier, 34293 Montpellier, France.
Department of Microbial and Molecular Pathogenesis, Texas A&M Health Science Center College of Medicine, Bryan, TX 77807-3260.
Proc Natl Acad Sci U S A. 2020 Jun 16;117(24):13708-13718. doi: 10.1073/pnas.1914892117. Epub 2020 Jun 1.
The Q fever agent uses a defect in organelle trafficking/intracellular multiplication (Dot/Icm) type 4b secretion system (T4SS) to silence the host innate immune response during infection. By investigating effector proteins containing eukaryotic-like domains, here we identify NopA (nucleolar protein A), which displays four regulator of chromosome condensation (RCC) repeats, homologous to those found in the eukaryotic Ras-related nuclear protein (Ran) guanine nucleotide exchange factor (GEF) RCC1. Accordingly, NopA is found associated with the chromatin nuclear fraction of cells and uses the RCC-like domain to interact with Ran. Interestingly, NopA triggers an accumulation of Ran-GTP, which accumulates at nucleoli of transfected or infected cells, thus perturbing the nuclear import of transcription factors of the innate immune signaling pathway. Accordingly, qRT-PCR analysis on a panel of cytokines shows that cells exposed to the ::Tn or a Dot/Icm-defective ::Tn mutant strain present a functional innate immune response, as opposed to cells exposed to wild-type or the corresponding complemented strain. Thus, NopA is an important regulator of the innate immune response allowing to behave as a stealth pathogen.
Q热病原体利用细胞器运输/细胞内增殖缺陷型（Dot/Icm）4b型分泌系统（T4SS）在感染期间使宿主先天免疫反应沉默。通过研究含有类真核结构域的效应蛋白，我们在此鉴定出核仁蛋白A（NopA），它具有四个染色体凝聚调节因子（RCC）重复序列，与真核Ras相关核蛋白（Ran）鸟嘌呤核苷酸交换因子（GEF）RCC1中的重复序列同源。因此，发现NopA与细胞的染色质核部分相关，并利用类RCC结构域与Ran相互作用。有趣的是，NopA触发Ran-GTP的积累，其在转染或感染细胞的核仁处积累，从而扰乱先天免疫信号通路转录因子的核输入。因此，对一组细胞因子的qRT-PCR分析表明，与暴露于野生型或相应互补菌株的细胞相反，暴露于::Tn或Dot/Icm缺陷型::Tn突变菌株的细胞呈现功能性先天免疫反应。因此，NopA是先天免疫反应的重要调节因子，使病原体能够表现为隐性病原体。
